destabilization-medial-meniscus-cartilage-scratch-murine-model

Destabilization of the Medial Meniscus and Cartilage Scratch Murine Model of Accelerated Osteoarthritis

Osteoarthritis is the most prevalent musculoskeletal disease in people over 45, leading to an increasing economic and societal cost. Animal models are ...

University of the West of Scotland

Proteinase-activated receptor-2 (PAR(2)) has been implicated in inflammatory articular pathology. Using the collagen-induced arthritis model (CIA) the authors have explored the capacity of PAR(2) to regulate adaptive immune pathways that could promote autoimmune mediated articular damage.

Immunomodulatory role of proteinase-activated receptor-2.

Rheumatoid arthritis (RA) is associated with high cardiovascular mortality. Impaired endothelial cell (EC) function and elevated angiotensin II levels may be central to the link between vascular dysfunction and RA. Here we investigated the action of angiotensin type 1 receptor (AT1R) blockade on endothelium-dependent relaxation of the isolated saphenous artery in a rat model of monoarthritis.

Angiotensin II Type 1 receptor blockade protects endothelium-derived hyperpolarising factor-mediated relaxation in a rat model of monoarthritis.

Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.

A role for endothelium-derived constricting factors (EDCF), and the angiotensin II type 1 receptor (AT1R) pathway, in the vascular impairment found in the rat Freund's complete adjuvant (FCA)-model of rheumatoid arthritis (RA) was examined. FCA arthritis was induced in rats±losartan. Vehicle-treated rats served as controls. Knee-joint swelling and red blood cell (RBC) aggregation were measured as indicators of inflammation and endothelium reactivity assessed by response to acetylcholine (ACh) on aortic rings. Results show that knee-joint swelling and RBC aggregation were elevated in the FCA+vehicle group and restored to control levels in the FCA+losartan-treated animals. ACh-induced relaxation of aortic rings taken from FCA+vehicle animals was significantly impaired compared to vehicle-controls and this vasoreactivity was restored to control levels in the FCA+losartan-treated group. Further examination of aorta from the FCA+vehicle animals revealed an EDCF that was reliant on cyclooxygenase-2 (but not cyclooxygenase-1), generation of superoxide anion generation (but not hydrogen peroxide) and activation of thromboxane-prostanoid receptor. Losartan administration in vivo or ex vivo (to aortic rings) prevented the generation of the EDCF. In summary, this is the first evidence of an EDCF in a model of RA and identifies this mechanism as potentially significant in the cardiovascular disorder associated with the disease.

Endothelium-derived contraction in a model of rheumatoid arthritis is mediated via angiotensin II type 1 receptors.

Protease-activated receptor-2 (PAR2) is one member of a small family of transmembrane, G-protein-coupled receptors. These receptors are activated  cleavage of their N terminus by serine proteases (e.g., tryptase), unveiling an N terminus tethered ligand which binds to the second extracellular loop of the receptor. Increasing evidence has emerged identifying key pathophysiological roles for PAR2 in both rheumatoid arthritis (RA) and osteoarthritis (OA). Importantly, this includes both pro-inflammatory and destructive roles. For example, in murine models of RA, the associated synovitis, cartilage degradation, and subsequent bone erosion are all significantly reduced in the absence of PAR2. Similarly, in experimental models of OA, PAR2 disruption confers protection against cartilage degradation, subchondral bone osteosclerosis, and osteophyte formation. This review focuses on the role of PAR2 in rheumatic disease and its potential as an important therapeutic target for treating pain and joint degradation.

Rheumatic Disease: Protease-Activated Receptor-2 in Synovial Joint Pathobiology.

The aim of this study was to determine the presence of protease-activated receptor 2 (PAR2) and matriptase proteins and quantify PAR2 and matriptase mRNA expression in the articular cartilage and synovial membrane of cats with and without osteoarthritis (OA).

Protease activated receptor 2 and matriptase expression in the joints of cats with and without osteoarthritis.

Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis.

Article	Year
Immunomodulatory role of proteinase-activated receptor-2. Annals of the rheumatic diseases\| PubMed ID: 22563031	2012
Angiotensin II Type 1 receptor blockade protects endothelium-derived hyperpolarising factor-mediated relaxation in a rat model of monoarthritis. Life sciences\| PubMed ID: 23643673	2013
Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology. Annals of the rheumatic diseases\| PubMed ID: 26698846	2016
Endothelium-derived contraction in a model of rheumatoid arthritis is mediated via angiotensin II type 1 receptors. Vascular pharmacology\| PubMed ID: 29122658	2018
Rheumatic Disease: Protease-Activated Receptor-2 in Synovial Joint Pathobiology. Frontiers in endocrinology\| PubMed ID: 29875735	2018
Protease activated receptor 2 and matriptase expression in the joints of cats with and without osteoarthritis. Journal of feline medicine and surgery\| PubMed ID: 33284033	2021
Losartan protects endothelium-dependent relaxation in vivo in a murine model of rheumatoid arthritis. European journal of pharmacology\| PubMed ID: 33984299	2021

Lynette Dunning

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